Synthetic Lethal Targeting of CREBBP/EP300 in Head and Neck Squamous Cell Carcinoma

CREBBP/EP300 在头颈鳞状细胞癌中的合成致死靶向

• 批准号: 10804966
• 负责人: Curtis Pickering
• 金额: $ 56.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10804966
• 关键词: Acetyltransferase; Aerodigestive Tract; Apoptotic; Binding; Biological Markers; Bromodomain; CREBBP gene; Cell Death; Cell Line; Cells; Cessation of life; Chemicals; Chromatin; Clinic; Clinical; Clinical Trials; DNA Damage; DNA Repair; DNA Sequence Alteration; Data; Dose; EP300 gene; Genes; Genetic Transcription; Genomics; Global Change; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histone Acetylation; In Vitro; Knock-out; Link; Measures; Mediating; Mutate; Mutation; Oncogenic; Outcome; PLK1 gene; Pathway interactions; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Platinum; Pre-Clinical Model; Protein Acetylation; Proteins; Radiation; Radiation therapy; Role; Schedule; Site; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Translating; Translations; Treatment Failure; Tumor Suppressor Genes; Tumor-Suppressor Gene Inactivation; advanced disease; candidate marker; cell type; comparative; cytotoxic; cytotoxicity; dosage; experimental study; functional genomics; genomic biomarker; histone acetyltransferase; improved; in vivo; in vivo evaluation; inhibitor; knock-down; mutant; new therapeutic target; novel; preclinical study; radiation response; response; response biomarker; side effect; small molecule; targeted agent; targeted biomarker; targeted treatment; therapeutic target; tumor

Head and neck squamous cell carcinomas (HNSCC) are a diverse group of tumors from the upper aerodigestive tract with relatively poor outcomes and limited targeted therapeutic options. Most patients are treated with a combination of DNA damaging agents (platinum, XRT). Recent genomic characterization of these tumors has not identified targetable oncogenic drivers, thus emphasizing the need to develop rational genomic-based approaches to increase sensitivity to treatments that induce DNA damage. We performed an in vivo functional genomic screen in genomically characterized HNSCC cell lines alone or in combination with DNA damaging agents. Knock-down of CREBBP or EP300 was identified as a potential mechanism to sensitize cells to the DNA damage response. CREBBP and EP300 are homologous multifunctional bromodomain-containing acetyltransferases that can regulate many proteins and pathways. Importantly, CREBBP and EP300 are mutated in 13% of HNSCC and sensitivity seems to be associated with those alterations, suggesting a synthetic cytotoxicity relationship. Additionally, these genes are druggable and small molecule inhibition of CREBBP increases DNA damage induction and persistence in response to radiation treatment and increased apoptotic cell death. We hypothesize that the CREBBP/EP300 pathway is both a biomarker and a therapeutically relevant target to sensitize HNSCC to currently used DNA damaging treatments. We propose to examine the genomic basis for this synthetic cytotoxicity and understand how mutations modulate the phenotype. We will also identify global changes to histone acetylation caused by modulation of CREBBP or EP300 and aim to understand how those changes impact the response to DNA damage. Additionally, therapeutic agents that modulate these genes will be tested for their efficacy in preclinical models with the goal of generating sufficient data to justify a clinical trial. Finally, we will perform another in vivo screen to identify other targets that can sensitize to inhibition of CREBBP with reduced toxicity. Overall, this project will examine an exciting new therapeutic target and candidate biomarker for a tumor type that is driven by loss of tumor suppressor genes and has proven difficult to target.

头部和颈部鳞状细胞癌（HNSCC）是从上部多样的肿瘤 消化道的结果相对较差，靶向治疗方案有限。大多数患者是 用DNA破坏剂（铂，XRT）的组合处理。最近的基因组表征 这些肿瘤尚未确定可靶向的致癌驱动因素，因此强调了发展理性的需求 基于基因组的方法，以增加对诱导DNA损伤的治疗的敏感性。我们表演了 单独或与之结合 DNA破坏代理。将CREBBP或EP300的敲低是一种潜在的机制 将细胞敏感到DNA损伤反应。 CREBBP和EP300是同源的多功能 可以调节许多蛋白质和途径的含溴群的乙酰转移酶。重要的是， CREBBP和EP300在13％的HNSCC中突变，敏感性似乎与之相关 改变，表明合成细胞毒性关系。此外，这些基因是可药的，很小 分子抑制CREBBP会增加DNA损伤的诱导和持续性，以响应辐射 治疗并增加凋亡细胞死亡。我们假设CREBBP/EP300途径都是 生物标志物和具有治疗相关的靶标，以使HNSCC敏感到当前使用DNA损害 治疗。我们建议检查这种合成细胞毒性的基因组基础，并了解如何 突变调节表型。我们还将确定由组蛋白乙酰化的全球变化 CREBBP或EP300的调节，旨在了解这些变化如何影响对DNA的反应 损害。此外，调节这些基因的治疗剂将在其在 临床前模型的目的是生成足够的数据以证明临床试验合理。最后，我们将表演 另一个体内筛选，以识别可以降低毒性降低CREBBP的其他靶标。 总体而言，该项目将检查令人兴奋的新治疗靶标和候选生物标志物的肿瘤类型 这是由于肿瘤抑制基因的丧失而驱动的，事实证明很难靶向。